This invention relates to the pharmaceutical therapeutic agent 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (celecoxib) of formula I 
specifically to a new crystalline form of celecoxib with improved properties. This invention further relates to a method for the production of this crystalline form of the agent.
Since prostaglandins play a major role in the inflammation process, the discovery of non-steroidal anti-inflammatory drugs (NSAIDs) has focused on the inhibition of prostaglandin production, especially PGG2, PGH2 and PGC2 production. The use of NSAIDs in the treatment of pain and swelling associated with the inflammation tends to cause side effects by affecting other prostaglandin regulated processes. Thus NSAIDs tend to cause significant side effects including ulcers.
Previous NSAIDs have been found to inhibit some enzymes including cyclooxygenase. Recently, an inducible form of cyclooxygenase associated with inflammation known as cyclooxygenase II (COX-2) or prostaglandin G/M synthase II has been found to exist. This enzyme is more effective in reducing inflammation, causing fewer and less drastic side effects.
Several compounds selectively inhibiting cyclooxygenase II are described in U.S. Pat. Nos. 5,380,738, 5,344,991, 5,393,790, 5,466,823, 5,434,178, 5,474,995, 5,510,368, and International Applications WO 96/06840, 96/03388, 96/03387, 95/15316, 94/15932, 94/27980, 95/00501, 94/13635, 94/20480 and 94/26731.
Certain substituted pyrazolylbenzenesulfonamides, specifically celecoxib (4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide) as selective COX-2 inhibitor and their preparation have been described in International Application WO 95/15316. In addition, an efficient preparation of 3-haloalkyl-1H-pyrazoles in a one-pot synthesis which is suitable for large-scale process has been described in International Application WO 96/37476.
International Application No. WO 00/32189 discloses specific celecoxib compositions. In this document a number of problems concerning the formulation of this agent, inter alia, its cohesiveness, low bulk density, low compressibility, poor solubility, etc., are described. According to this document, these disadvantages are caused by the crystal structure of celecoxib. Unformulated celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses into a monolith mass upon compression in a tablet die, which leads to problems in blending the agent uniformly. Further, low bulk density causes problems in processing the small quantities required in the formulation of pharmaceutical compositions.
It has now surprisingly been discovered that celecoxib may exist at least in two crystalline forms, hereinafter designated as Form I and Form II, having different properties.
Certain organic compounds can exist in several different crystal forms, which can have different chemical and physical properties, such as density, hardness, flow properties, etc. Therefore, new crystal forms of existing compounds are of great interest. The new crystal form of celecoxib reported herein provides improved properties, making it possible to overcome the problems described in the prior art. Since the new crystal form does not have the disadvantages of the known needle-like crystals, it overcomes the problems disclosed e.g. in WO 00/32189.
The object of the present invention, therefore, is to provide a new crystalline form of celecoxib which avoids the problems produced by the known, needle-like crystalline form. The solution of this object is provided by the new crystalline form of celecoxib as disclosed herein, which we have called xe2x80x9cForm Ixe2x80x9d of celecoxib, and by the corresponding production method, as also described herein.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specification.
The invention accordingly comprises a composition of matter possessing the characteristics, properties, and the relation of constituents which will be exemplified in the composition hereinafter described, and the scope of the invention will be indicated in the claims.